The disease classification neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of progressive neurodegenerative disorders characterized by brain iron deposits in the basal ganglia. For about half of the cases, the molecular basis is currently unknown. We used homozygosity mapping followed by candidate gene sequencing to identify a homozygous 11 bp deletion in the orphan gene C19orf12. Mutation screening of 23 ideopathic NBIA index cases revealed two mutated alleles in 18 of them, and one loss-of-function mutation is the most prevalent. We also identified compound heterozygous missense mutations in a case initially diagnosed with Parkinson disease at age 49. Psychiatric signs, optic atrophy, and motor axonal neuropathy were common findings. Compared to the most prevalent NBIA subtype, pantothenate kinase associated neurodegeneration (PKAN), individuals with two C19orf12 mutations were older at age of onset and the disease progressed more slowly. A polyclonal antibody against the predicted membrane spanning protein showed a mitochondrial localization. A histopathological examination in a single autopsy case detected Lewy bodies, tangles, spheroids, and tau pathology. The mitochondrial localization together with the immunohistopathological findings suggests a pathomechanistic overlap with common forms of neurodegenerative disorders.

The transcription factor NF-kappaB is a key regulator of inflammation and cell survival. NF-kappaB is activated by cerebral ischemia in neurons and glia, but its function is controversial. To inhibit NF-kappaB selectively in neurons and glial cells, we have generated transgenic mice that express the IkappaBalpha superrepressor (IkappaBalpha mutated at serine-32 and serine-36, IkappaBalpha-SR) under transcriptional control of the neuron-specific enolase (NSE) and the glial fibrillary acidic protein (GFAP) promoter, respectively. In primary cortical neurons of NSE-IkappaBalpha-SR mice, NF-kappaB activity was partially inhibited. To assess NF-kappaB activity in vivo after permanent middle cerebral artery occlusion (MCAO), we measured the expression of NF-kappaB target genes by real-time polymerase chain reaction (PCR). The induction of c-myc and transforming growth factor-beta2 by cerebral ischemia was inhibited by neuronal expression of IkappaBalpha-SR, whereas induction of GFAP by MCAO was reduced by astrocytic expression of IkappaBalpha-SR. Neuronal, but not astrocytic, expression of the NF-kappaB inhibitor reduced both infarct size and cell death 48 hours after permanent MCAO. In summary, the data show that NF-kappaB is activated in neurons and astrocytes during cerebral ischemia and that NF-kappaB activation in neurons contributes to the ischemic damage.

IL-6 and its receptor(s) are found in the CNS in health and disease. Cellular sources are glial cells and neurons. Glial production of IL-6 has intensively been studied, but comparatively little is known about the induction of IL-6 in neurons. Emerging evidence suggests that IL-6 possesses neurotrophic properties. Recent data show that neuronal IL-6 expression is induced by excitatory amino acids or membrane depolarization. This implicates that IL-6 is produced not only under pathological conditions but may play a critical role as a physiological neuromodulator that is induced by neuronal activity and regulates brain functions. In the following article, the authors review the current data on IL-6 expression in neurons, with special reference to the induction of IL-6 by neuronal activity. They discuss its direct and indirect effects as a neuromodulator and speculate about the possible function of IL-6 as a physiological regulatory molecule and as a neuroprotective agent in brain pathology.

Although the function of fever is still unclear, it is now beyond doubt that body temperature influences the outcome of brain damage. An elevated body temperature is often found in stroke patients and denotes a bad prognosis. However, the pathophysiologic basis and treatment options of elevated body temperature after stroke are still unknown. Cerebral ischemia rapidly induced neuronal interleukin-6 (IL-6) expression in mice. In IL-6-deficient mice, body temperature was markedly decreased after middle cerebral artery occlusion (MCAO), but infarct size was comparable to that in control mice. If body temperature was controlled by external warming after MCAO, IL-6-deficient mice had a reduced survival, worse neurologic status, and larger infarcts than control animals. In cell culture, IL-6 exerted an antiapoptotic and neuroprotective effect. These data suggest that IL-6 is a key regulator of body temperature and an endogenous neuroprotectant in cerebral ischemia. Neuroprotective properties apparently compensate for its pyretic action after MCAO and enhance the safety of this endogenous pyrogen.

Background: Due to its strong water binding potential, hyaluronic acid (HA) is a well-known active ingredient for cosmetic applications. However, based on its varying molecular size, skin penetration of HA may be limited. Recent studies have demonstrated that low-molecular-weight HA (LMW HA) may show a certain proinflammatory activity. We thus aimed to characterize an LMW-sized HA molecule that combines strong anti-aging abilities with efficient skin penetration but lacks potential proinflammatory effects. Methods: Total RNA and total protein were isolated from reconstituted human epidermis following incubation with HAs of various molecular weights (20, 50, 130, 300, 800 and 1,500 kDa). Tumor necrosis factor-α expression was determined using quantitative PCR. Genomic and proteomic expression of various junctional proteins was determined using Affymetrix and common Western blotting techniques. Results: LMWHA of approximately 50 kDa did not significantly alter tumor necrosis factor-α expression compared to 20-kDa HA, but revealed significantly higher skin penetration rates than larger sized HA associated with increased expression of genes and proteins known to be involved in tight junction formation and keratinocyte cohesion. Conclusion: LMW HA of approximately 50 kDa shows better penetration abilities than larger-sized HA. In addition, LMW HA influences the expression of various genes including those contributing to keratinocyte differentiation and formation of intercellular tight junction complexes without showing proinflammatory activity. These observations contribute to current knowledge on the effects of LMW HA on keratinocyte biology and cutaneous physiology.

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Summary:Although the function of fever is still unclear, it is now beyond doubt that body temperature influences the outcome of brain damage. An elevated body temperature is often found in stroke patients and denotes a bad prognosis. However, the pathophysiologic basis and treatment options of elevated body temperature after stroke are still unknown. Cerebral ischemia rapidly induced neuronal interleukin-6 (IL-6) expression in mice. In IL-6-deficient mice, body temperature was markedly decreased after middle cerebral artery occlusion (MCAO), but infarct size was comparable to that in control mice. If body temperature was controlled by external warming after MCAO, IL-6-deficient mice had a reduced survival, worse neurologic status, and larger infarcts than control animals. In cell culture, IL-6 exerted an antiapoptotic and neuroprotective effect. These data suggest that IL-6 is a key regulator of body temperature and an endogenous neuroprotectant in cerebral ischemia. Neuroprotective properties apparently compensate for its pyretic action after MCAO and enhance the safety of this endogenous pyrogen.

Keratinocyte sphingolipids are structural elements of epidermal permeability barrier and potential regulators of epidermal functions. We tested the influence of sphingoid bases sphinganine, sphingosine and phytosphingosine on in vitro keratinocyte differentiation. Lipidomic and transcriptomic analysis after treatment emphasizes sphinganine and phytosphingosine as potent modulators of keratinocyte differentiation and lipid metabolism. Sphinganine treatment regulated differentiation and sphingolipid metabolism-related genes, and also increased all major ceramide species. Sphingosine treatment increased ceramide and phytoceramide pools without changes in dihydroceramides. Phytosphingosine treatment markedly increased phytoceramide pools without raising ceramide or dihydroceramide levels. Sphinganine treatment increased specifically very long chain ceramides essential for intact barrier function. In summary, sphingoid bases, especially sphinganine, promote differentiation and ceramide production in keratinocytes. Free sphinganine may serve as a dermatological and cosmetic agent by enhancing formation and maintenance of an intact epidermal lipid barrier, with beneficial effects for skin and hair care applications.Abbreviations: FA, fatty acid; SpB, sphingoid base.